Novel esterified cellulose ethers of low viscosity

ABSTRACT

Esterified cellulose ethers which comprise (i) aliphatic monovalent acyl groups or (ii) groups of the formula —C(O)—R—COOA, wherein R is a divalent aliphatic or aromatic hydrocarbon group and A is hydrogen or a cation, or (iii) a combination of aliphatic monovalent acyl groups and groups of the formula —C(O)—R—COOA, which have a viscosity of up to 2.33 mPa·s, measured as a 2.0 wt % solution of the esterified cellulose ether in 0.43 wt % aqueous NaOH at 20° C., and which have a viscosity of up to 13 mPao·s, measured as a 10 wt % solution of the esterified cellulose ether in acetone at 20° C. are useful for preparing solid dispersions comprising drugs.

This invention concerns novel esterified cellulose ethers, soliddispersions of an active ingredient in such esterified cellulose ether,as well as liquid compositions, coated dosage forms and capsulescomprising such esterified cellulose ether.

Esters of cellulose ethers, their uses and processes for preparing themare generally known in the art. Known methods of producing celluloseether-esters include the reaction of a cellulose ether with an aliphaticmonocarboxylic acid anhydride or a dicarboxylic acid anhydride or acombination thereof, for example as described in U.S. Pat. Nos.4,226,981 and 4,365,060.

Various known esterified cellulose ethers are useful as enteric polymersfor pharmaceutical dosage forms, such as methylcellulose phthalate,hydroxypropyl methylcellulose phthalate, methylcellulose succinate, orhydroxypropyl methylcellulose succinate. Dosage forms coated with suchpolymers protect the drug from inactivation or degradation in the acidicenvironment or prevent irritation of the stomach by the drug. U.S. Pat.No. 4,365,060 discloses enterosoluble capsules which are said to haveexcellent enterosolubility behavior.

U.S. Pat. No. 5,776,501 teaches the usage of a water-soluble celluloseether having a viscosity of 3 to 10 cp (mPa·s), determined as a 2% byweight aqueous solution. If the viscosity is less than 3 cp, the finallyobtained coating film for solid enteric pharmaceutical preparations isinsufficient in strength, while if it exceeds 10 cp, the viscosityobserved when it is dissolved in a solvent to carry out a substitutionreaction becomes extremely high.

US Patent Application Publication No. 2004/0152886 discloses theproduction of hydroxypropyl methylcellulose phthalate starting fromhydroxypropyl methylcellulose having a viscosity of 3 to 20 cp, measuredas a 2 wt. % aqueous solution.

International patent applications WO 2005/115330 and WO 2011/159626disclose the preparation of hydroxypropyl methylcellulose acetatesuccinate (HPMCAS). HPMC having an apparent viscosity of 2.4 to 3.6 cp(mPa·s) is recommended as a starting material. Alternatively, a HPMCstarting material of 600 to 60,000 Daltons, preferably 3000 to 50,000Daltons, more preferably 6,000 to 30,000 Daltons is recommended.According to Keary [Keary, C. M.; Carbohydrate Polymers 45 (2001)293-303, Tables 7 and 8] HPMC having a weight average molecular weightof about 85-100 kDa has a viscosity of about 50 mPa×s, determined as a2% by weight aqueous solution.

A large number of presently known drugs have a low solubility in water,so that complex techniques are required to prepare a dosage form. Oneknown method includes dissolving such drug together with apharmaceutically acceptable water-soluble polymer, such as an esterifiedcellulose ether, in an organic solvent that is optionally blended withwater, and to spray-dry the solution. The esterified cellulose ether isaimed at reducing the crystallinity of the drug, thereby minimizing theactivation energy necessary for the dissolution of the drug, as well asestablishing hydrophilic conditions around the drug molecules, therebyimproving the solubility of the drug itself to increase itsbioavailability, i.e., its in vivo absorption by an individual uponingestion.

Unfortunately, the known esterified cellulose ethers often cannot beefficiently used in spray-drying operations. When known esterifiedcellulose ethers are dissolved at a high concentration in an organicsolvent, such as a concentration of 7-10 weight percent, and suchsolution is combined with a drug and spray-dried, the resulting solutionhas a high viscosity, is difficult to be spray-dried and tends to clogthe spray-drying device. When a highly diluted solution is utilized, anunduly high amount of organic solvent has to be evaporated. Similarproblems occur when esterified cellulose ethers are dissolved in organicsolvents and used for coating purposes, such as tablet coatings.

Accordingly, it would be highly desirable to find new esterifiedcellulose ethers which can be efficiently used in spray-drying andcoating processes. It would be particularly desirable to find such newesterified cellulose ethers which are suitable for improving thesolubility of drugs.

One aspect of the present invention is an esterified cellulose etherwhich comprises (i) aliphatic monovalent acyl groups or (ii) groups ofthe formula —C(O)—R—COOA, wherein R is a divalent aliphatic or aromatichydrocarbon group and A is hydrogen or a cation, or (iii) a combinationof aliphatic monovalent acyl groups and groups of the formula—C(O)—R—COOA, which has a viscosity of up to 2.33 mPa·s, measured as a2.0 wt % solution of the esterified cellulose ether in 0.43 wt % aqueousNaOH at 20° C., and which has a viscosity of up to 13 mPa·s, measured asa 10 wt % solution of the esterified cellulose ether in acetone at 20°C.

Another aspect of the present invention is a composition which comprisesa liquid diluent and at least one above-described esterified celluloseether.

Yet another aspect of the present invention is a solid dispersion of atleast one active ingredient in at least one above-described esterifiedcellulose ether.

Yet another aspect of the present invention is a dosage form which iscoated with at least one above-described esterified cellulose ether.

Yet another aspect of the present invention is a capsule shell whichcomprises at least one above-described esterified cellulose ether.

The esterified cellulose ether has a cellulose backbone having β-1,4glycosidically bound D-glucopyranose repeating units, designated asanhydroglucose units in the context of this invention. The esterifiedcellulose ether preferably is an esterified alkyl cellulose,hydroxyalkyl cellulose or hydroxyalkyl alkylcellulose. This means thatin the esterified cellulose ether of the present invention, at least apart of the hydroxyl groups of the anhydroglucose units are substitutedby alkoxyl groups or hydroxyalkoxyl groups or a combination of alkoxyland hydroxyalkoxyl groups. The hydroxyalkoxyl groups are typicallyhydroxymethoxyl, hydroxyethoxyl and/or hydroxypropoxyl groups.Hydroxyethoxyl and/or hydroxypropoxyl groups are preferred. Typicallyone or two kinds of hydroxyalkoxyl groups are present in the esterifiedcellulose ether. Preferably a single kind of hydroxyalkoxyl group, morepreferably hydroxypropoxyl, is present. The alkoxyl groups are typicallymethoxyl, ethoxyl and/or propoxyl groups. Methoxyl groups are preferred.Illustrative of the above-defined esterified cellulose ethers areesterified alkylcelluloses, such as esterified methylcelluloses,ethylcelluloses, and propylcelluloses; esterifiedhydroxyalkylcelluloses, such as esterified hydroxyethylcelluloses,hydroxypropylcelluloses, and hydroxybutylcelluloses; and esterifiedhydroxyalkyl alkylcelluloses, such as esterified hydroxyethylmethylcelluloses, hydroxymethyl ethylcelluloses, ethylhydroxyethylcelluloses, hydroxypropyl methylcelluloses, hydroxypropylethylcelluloses, hydroxybutyl methylcelluloses, and hydroxybutylethylcelluloses; and those having two or more hydroxyalkyl groups, suchas esterified hydroxyethylhydroxypropyl methylcelluloses. Mostpreferably, the esterified cellulose ether is an esterified hydroxyalkylmethylcellulose, such as hydroxypropyl methylcellulose.

The degree of the substitution of hydroxyl groups of the anhydroglucoseunits by hydroxyalkoxyl groups is expressed by the molar substitution ofhydroxyalkoxyl groups, the MS(hydroxyalkoxyl). The MS(hydroxyalkoxyl) isthe average number of moles of hydroxyalkoxyl groups per anhydroglucoseunit in the esterified cellulose ether. It is to be understood thatduring the hydroxyalkylation reaction the hydroxyl group of ahydroxyalkoxyl group bound to the cellulose backbone can be furtheretherified by an alkylating agent, e.g. a methylating agent, and/or ahydroxyalkylating agent. Multiple subsequent hydroxyalkylationetherification reactions with respect to the same carbon atom positionof an anhydroglucose unit yields a side chain, wherein multiplehydroxyalkoxyl groups are covalently bound to each other by ether bonds,each side chain as a whole forming a hydroxyalkoxyl substituent to thecellulose backbone.

The term “hydroxyalkoxyl groups” thus has to be interpreted in thecontext of the MS(hydroxyalkoxyl) as referring to the hydroxyalkoxylgroups as the constituting units of hydroxyalkoxyl substituents, whicheither comprise a single hydroxyalkoxyl group or a side chain asoutlined above, wherein two or more hydroxyalkoxyl units are covalentlybound to each other by ether bonding. Within this definition it is notimportant whether the terminal hydroxyl group of a hydroxyalkoxylsubstituent is further alkylated or not; both alkylated andnon-alkylated hydroxyalkoxyl substituents are included for thedetermination of MS(hydroxyalkoxyl). The esterified cellulose ether ofthe invention generally has a molar substitution of hydroxyalkoxylgroups in the range 0.05 to 1.00, preferably 0.08 to 0.90, morepreferably 0.12 to 0.70, most preferably 0.15 to 0.60, and particularly0.21 to 0.50.

The average number of hydroxyl groups substituted by alkoxyl groups,such as methoxyl groups, per anhydroglucose unit, is designated as thedegree of substitution of alkoxyl groups, DS(alkoxyl). In theabove-given definition of DS, the term “hydroxyl groups substituted byalkoxyl groups” is to be construed within the present invention toinclude not only alkylated hydroxyl groups directly bound to the carbonatoms of the cellulose backbone, but also alkylated hydroxyl groups ofhydroxyalkoxyl substituents bound to the cellulose backbone. Theesterified cellulose ethers according to this invention preferably havea DS(alkoxyl) in the range of 1.0 to 2.5, more preferably from 1.1 to2.4, even more preferably from 1.2 to 2.2, most preferably from 1.6 to2.05, and particularly from 1.7 to 2.05.

Most preferably the esterified cellulose ether is an esterifiedhydroxypropyl methylcellulose having a DS(methoxyl) within the rangesindicated above for DS(alkoxyl) and an MS(hydroxypropoxyl) within theranges indicated above for MS(hydroxyalkoxyl).

The esterified cellulose ether of the present invention has (i)aliphatic monovalent acyl groups or (ii) groups of the formula—C(O)—R—COOA, wherein R is a divalent aliphatic or aromatic hydrocarbongroup and A is hydrogen or a cation, or (iii) a combination of aliphaticmonovalent acyl groups and groups of the formula —C(O)—R—COOA. Thecation preferably is an ammonium cation, such as NH₄ ⁺ or an alkalimetal ion, such as the sodium or potassium ion, more preferably thesodium ion. Most preferably, A is hydrogen.

The aliphatic monovalent acyl groups are preferably selected from thegroup consisting of acetyl, propionyl, and butyryl, such as n-butyryl ori-butyryl.

Preferred groups of the formula —C(O)—R—COOA are

—C(O)—CH₂—CH₂—COOA, such as —C(O)—CH₂—CH₂—COOH or —C(O)—CH₂—CH₂—COO⁻Na⁺,—C(O)—CH═CH—COOA, such as —C(O)—CH═CH—COOH or —C(O)—CH═CH—COO⁻Na⁺, or—C(O)—C₆H₄—COOA, such as —C(O)—C₆H₄—COOH or —C(O)—C₆H₄—COO⁻Na⁺.

In the groups of formula —C(O)—C₆H₄—COOA the carbonyl group and thecarboxylic group are preferably arranged in ortho-positions.

Preferred esterified cellulose ethers are

i) HPMCXY, wherein HPMC is hydroxypropyl methyl cellulose, X is A(acetate), or X is B (butyrate) or X is Pr (propionate) and Y is S(succinate), or Y is P (phthalate) or Y is M (maleate), such ashydroxypropyl methyl cellulose acetate phthalate (HPMCAP), hydroxypropylmethyl cellulose acetate maleate (HPMCAM), or hydroxypropylmethylcellulose acetate succinate (HPMCAS), or

ii) hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropylcellulose acetate succinate (HPCAS), hydroxybutyl methyl cellulosepropionate succinate (HBMCPrS), hydroxyethyl hydroxypropyl cellulosepropionate succinate (HEHPCPrS); and methyl cellulose acetate succinate(MCAS).

Hydroxypropyl methylcellulose acetate succinate (HPMCAS) is the mostpreferred esterified cellulose ether.

The esterified cellulose ethers generally have a degree of substitutionof aliphatic monovalent acyl groups, such as acetyl, propionyl, orbutyryl groups, of 0 to 1.75, preferably of 0.05 to 1.50, morepreferably of 0.10 to 1.25, and most preferably of 0.20 to 1.00.

The esterified cellulose ethers generally have a degree of substitutionof groups of formula —C(O)—R—COOA, such as succinoyl, of 0.05 to 1.6,preferably of 0.05 to 1.30, more preferably of 0.05 to 1.00, and mostpreferably of 0.10 to 0.70 or even 0.10 to 0.60.

The sum of i) the degree of substitution of aliphatic monovalent acylgroups and ii) the degree of substitution of groups of formula—C(O)—R—COOA is generally from 0.05 to 2.0, preferably from 0.10 to 1.4,more preferably from 0.20 to 1.15, most preferably from 0.30 to 1.10 andparticularly from 0.40 to 1.00.

The content of the acetate and succinate ester groups is determinedaccording to “Hypromellose Acetate Succinate”, United StatesPharmacopeia and National Formulary, NF 29, pp. 1548-1550. Reportedvalues are corrected for volatiles (determined as described in section“loss on drying” in the above HPMCAS monograph). The method may be usedin analogue manner to determine the content of propionyl, butyryl,phthalyl and other ester groups.

The content of ether groups in the esterified cellulose ether isdetermined in the same manner as described for “Hypromellose”, UnitedStates Pharmacopeia and National Formulary, USP 35, pp 3467-3469.

The contents of ether and ester groups obtained by the above analysesare converted to DS and MS values of individual substituents accordingto the formulas below. The formulas may be used in analogue manner todetermine the DS and MS of substituents of other cellulose ether esters.

${\% \mspace{14mu} {cellulose}\mspace{14mu} {backbone}} = {100 - \left( {\% \mspace{14mu} {MeO}*\frac{{M\left( {OCH}_{3} \right)} - {M({OH})}}{M\left( {OCH}_{3} \right)}} \right) - \left( {\% \mspace{14mu} {HPO}*\frac{{M\left( {{OCH}_{2}{{CH}({OH})}{CH}_{3}} \right)} - {M({OH})}}{M\left( {{OCH}_{2}{{CH}({OH})}{CH}_{3}} \right)}} \right) - \left( {\% \mspace{14mu} {Acetyl}*\frac{{M\left( {COCH}_{3} \right)} - {M(H)}}{M\left( {COCH}_{3} \right)}} \right) - \left( {\% \mspace{14mu} {Succinoyl}*\frac{{M\left( {{COC}_{2}H_{4}{COOH}} \right)} - {M(H)}}{M\left( {{COC}_{2}H_{4}{COOH}} \right)}} \right)}$${{DS}({Me})} = {{\frac{\frac{\% \mspace{14mu} {MeO}}{M\left( {OCH}_{3} \right)}}{\frac{\% \mspace{14mu} {cellulose}\mspace{14mu} {backbone}}{M({AGU})}}\mspace{14mu} {{MS}({HP})}} = \frac{\frac{\% \mspace{14mu} {HOP}}{M({HOP})}}{\frac{\% \mspace{14mu} {cellulose}\mspace{14mu} {backbone}}{M({AGU})}}}$${{DS}({Acetyl})} = {{\frac{\frac{\% \mspace{14mu} {Acetyl}}{M({Acetyl})}}{\frac{\% \mspace{14mu} {cellulose}\mspace{14mu} {backbone}}{M({AGU})}}\mspace{14mu} {{DS}({Succinoyl})}} = \frac{\frac{\% \mspace{14mu} {Succinoyl}}{M({Succinoyl})}}{\frac{\% \mspace{14mu} {cellulose}\mspace{14mu} {backbone}}{M({AGU})}}}$M(MeO) = M(OCH₃) = 31.03  DaM(HPO) = M(OCH₂CH(OH)CH₃) = 75.09  DaM(Acetyl) = M(COCH₃) = 43.04  DaM(Succinoyl) = M(COC₂H₄COOH) = 101.08  DaM(AGU) = 162.14  Da  M(OH) = 17.008  Da  M(H) = 1.008  Da

By convention, the weight percent is an average weight percentage basedon the total weight of the cellulose repeat unit, including allsubstituents. The content of the methoxyl group is reported based on themass of the methoxyl group (i.e., —OCH₃). The content of thehydroxyalkoxyl group is reported based on the mass of the hydroxyalkoxylgroup (i.e., —O— alkylene-OH); such as hydroxypropoxyl (i.e.,—O—CH₂CH(CH₃)—OH). The content of the aliphatic monovalent acyl groupsis reported based on the mass of —C(O)—R₁ wherein R₁ is a monovalentaliphatic group, such as acetyl (—C(O)—CH₃). The content of the group offormula —C(O)—R—COOH is reported based on the mass of this group, suchas the mass of succinoyl groups (i.e., —C(O)—CH₂—CH₂—COOH).

The esterified cellulose ethers of the present invention have aviscosity of up to 2.33 mPa·s, or up to 2.25 mPa·s, preferably up to2.10 mPa·s, more preferably up to 1.95 mPa·s, even more preferably up to1.80 mPa·s, most preferably up to 1.70 mPa·s, and particularly up to1.55 mPa·s, measured as a 2.0 wt % solution of the esterified celluloseether in 0.43 wt.-% aqueous NaOH at 20° C. Generally the viscosity ofthe esterified cellulose ether is 1.20 mPa·s or more, typically 1.30mPa·s or more, and more typically 1.40 mPa·s or more, measured as a 2.0wt % solution of the esterified cellulose ether in 0.43 wt % aqueousNaOH at 20° C. The 2.0% by weight solution of the esterified celluloseether is prepared as described in“Hypromellose Acetate Succinate, UnitedStates Pharmacopeia and National Formulary, NF 29, pp. 1548-1550”,followed by an Ubbelohde viscosity measurement according to DIN51562-1:1999-01 (January 1999). It has been found that the viscosity ofthe esterified cellulose ether in 0.43 wt % aqueous NaOH is very similarto the viscosity of the cellulose ether which is useful as a startingmaterial for producing the esterified cellulose ether.

Moreover, the esterified cellulose ethers of the present invention havea viscosity of only up to 13 mPa·s, generally up to 12 mPa·s, preferablyup to 11 mPa·s, and more preferably up to 10 mPa·s, measured as a 10 wt% solution of the esterified cellulose ether in acetone at 20° C. Insome embodiments of the present invention, esterified cellulose etherscan be produced that have a viscosity of only up to 8.0 mPa·s,preferably only up to 6.5 mPa·s, more preferably only up to 5.0 mPa·s,most preferably only up to 4.0 mPa·s, and particularly only up to 3.0mPa·s, measured as a 10 wt % solution of the esterified cellulose etherin acetone at 20° C. The esterified cellulose ethers of the presentinvention typically have a viscosity of 1.50 mPa·s or more, moretypically of 1.65 mPa·s or more, and most typically of 1.80 mPa·s ormore, measured as a 10 wt % solution of the esterified cellulose etherin acetone at 20° C. In some embodiments of the present invention, theesterified cellulose ethers have a viscosity of 5.0 mPa·s or more, moretypically 6.5 mPa·s or more. The viscosity of the esterified celluloseethers of the present, measured as a 10 wt % solution in acetone, isconsiderably lower than the viscosity of known esterified celluloseethers in acetone. The low viscosity of the esterified cellulose ethersof the present invention is highly advantageous when a liquidcomposition comprising the esterified cellulose ether is subjected tospray-drying, for example for preparing solid dispersions comprising anactive ingredient and an esterified cellulose ether. The 10 wt %solution of the esterified cellulose ether in acetone can be prepared asin described in the Examples further below.

The average molecular weights of the esterified cellulose ethers of thepresent invention depends on various factors, such as the viscosity ofthe cellulose ether, measured as a 2.0 wt % solution in water at 20° C.,which is used for preparing the esterified cellulose ethers of thepresent invention, and the weight ratios between the cellulose ether,diluent and catalyst that are used in the esterification reaction, aswill be explained in more details below.

In one embodiment of the present invention the esterified celluloseethers generally have a weight average molecular weight M_(w) of from10,000 to 90,000 Dalton, or from 10,000 to 70,000 Dalton, or from 12,000to 50,000 Dalton. In this embodiment of the invention the esterifiedcellulose ethers generally have a number average molecular weight M_(n)of from 8000 to 20,000 Dalton or from 9000 to 18,000 Dalton and/or az-average molecular weight, M_(z), of from 20,000 to 900,000 Dalton orfrom 25,000 Dalton to 500,000 Dalton.

In another embodiment of the present invention the esterified celluloseethers generally have a weight average molecular weight M_(w) of from90,000 to 350,000 Dalton, or from 90,000 to 300,000 Dalton, or from100,000 to 250,000 Dalton, or from 110,000 to 200,000 Dalton. In thisembodiment of the invention the esterified cellulose ethers generallyhave a number average molecular weight M_(n) of from 8,000 Dalton to40,000 Dalton or from 9,000 Dalton to 35,000 Dalton and/or a z-averagemolecular weight, M_(z), of from 550,000 Dalton to 1,500,000 Dalton orfrom 600,000 Dalton to 1,000,000.

M_(w), M_(n) and M_(z) are measured according to Journal ofPharmaceutical and Biomedical Analysis 56 (2011) 743 using a mixture of40 parts by volume of acetonitrile and 60 parts by volume of aqueousbuffer containing 50 mM NaH₂PO₄ and 0.1 M NaNO₃ as mobile phase. Themobile phase is adjusted to a pH of 8.0. The measurement of M_(w), M_(n)and M_(z) is described in more details in the Examples.

The examples below describe how to prepare the esterified celluloseethers of the present invention. Some aspects of the process forproducing these esterified cellulose ethers will be described in moregeneral terms below.

The esterified cellulose ethers of the present invention are producedfrom a cellulose ether which has a viscosity of from 1.20 to 2.33 mPa·s,typically from 1.20 to 2.25 mPa·s, preferably from 1.20 to 2.10 mPa·s,more preferably from 1.20 to 1.95 mPa·s, even more preferably from 1.20to 1.80 mPa·s, most preferably from 1.20 to 1.70 mPa·s, and particularlyfrom 1.20 to 1.55 mPa·s, measured as a 2.0 wt % solution in water at 20°C. (+/−0.1° C.).

The 2.0% by weight solution of a cellulose ether in water is preparedaccording to United States Pharmacopeia (USP 35, “Hypromellose”, pages3467-3469), followed by an Ubbelohde viscosity measurement according toDIN 51562-1:1999-01 (January 1999). A low viscosity cellulose ether usedas a starting material allows for a good miscibility of the reactionmixture used for producing the esterified cellulose ethers resulting ina homogeneous reaction mixture. Preferably a cellulose ether is usedwhich has the type of ether groups and the degree(s) of substitution ofether groups as described further above. The above-described celluloseethers and their production are described in the international patentapplications WO2009061821 and WO2009/061815.

The cellulose ether is reacted with (i) an aliphatic monocarboxylic acidanhydride or (ii) a dicarboxylic acid anhydride or (iii) a combinationof an aliphatic monocarboxylic acid anhydride and a dicarboxylic acidanhydride. Preferred aliphatic monocarboxylic acid anhydrides areselected from the group consisting of acetic anhydride, butyricanhydride and propionic anhydride. Preferred dicarboxylic acidanhydrides are selected from the group consisting of succinic anhydride,maleic anhydride and phthalic anhydride. If a dicarboxylic acidanhydride and an aliphatic monocarboxylic acid anhydride are used incombination, the two anhydrides may be introduced into the reactionvessel at the same time or separately one after the other. The amount ofeach anhydride to be introduced into the reaction vessel is determineddepending on the desired degree of esterification to be obtained in thefinal product, usually being 1 to 10 times the stoichiometric amounts ofthe desired molar degree of substitution of the anhydroglucose units byesterification. If an anhydride of a dicarboxylic acid is used, themolar ratio between the anhydride of a dicarboxylic acid and theanhydroglucose units of cellulose ether generally is 0.1/1 or more, andpreferably 0.13/1 or more. The molar ratio between the anhydride of adicarboxylic acid and the anhydroglucose units of cellulose ethergenerally is 1.5/1 or less, and preferably 1/1 or less. If an anhydrideof a monocarboxylic acid is used, the molar ratio between the anhydrideof an aliphatic monocarboxylic acid and the anhydroglucose units of thecellulose ether generally is 0.9/1 or more, and preferably 1.0/1 ormore. The molar ratio between the anhydride of an aliphaticmonocarboxylic acid and the anhydroglucose units of the cellulose ethergenerally is 8/1 or less, preferably 6/1 or less, and more preferably4/1 or less. The molar number of anhydroglucose units of the celluloseether utilized in the process can be determined from the weight of thecellulose ether used as a starting material, by calculating the averagemolecular weight of the substituted anhydroglucose units from theDS(alkoxyl) and MS(hydroxyalkoxyl).

The esterification of the cellulose ether is preferably conducted in analiphatic carboxylic acid as a reaction diluent, such as acetic acid,propionic acid, or butyric acid. The reaction diluent can comprise minoramounts of other solvents or diluents which are liquid at roomtemperature and do not react with the cellulose ether, such as aromaticor aliphatic solvents like benzene, toluene, 1,4-dioxane, ortetrahydrofurane; or halogenated C₁-C₃ derivatives, like dichloromethane or dichloro methyl ether, but the amount of the aliphaticcarboxylic acid is preferably more than 50 percent, more preferably atleast 75 percent, and even more preferably at least 90 percent, based onthe total weight of the reaction diluent.

Most preferably the reaction diluent consists of an aliphatic carboxylicacid. Therefore, the esterification process is described below withreference to the use of an aliphatic carboxylic acid as reaction diluentalthough the process is not limited to it.

It has been found that the viscosity of an esterified cellulose ether,measured as a 10 wt % solution in acetone at 20° C., can be influencedby three major parameters of the esterification reaction: 1. theviscosity of the cellulose ether used as a starting material; 2. themolar ratio [aliphatic carboxylic acid/anhydroglucose units of celluloseether]; and 3. the molar ratio [esterification catalyst/anhydroglucoseunits of cellulose ether]. Based on the general teaching herein and themore specific teaching in the Examples, the skilled artisan knows how tochoose these three major parameters of the esterification reaction toarrive at the esterified cellulose ethers of the present invention.

Surprisingly, it has been found that an esterified cellulose ether witha significantly lower viscosity, measured as a 10 wt % solution inacetone, is obtained, when a cellulose ether is used as a startingmaterial which has a viscosity of from 1.20 to 2.33 mPa·s, measured as a2.0 wt % solution in water at 20° C., than when a cellulose ether of aviscosity of 3 mPa·s or more is used as disclosed in the prior art,while keeping the other reaction parameters constant. As illustrated bythe Examples and Comparative Examples, the viscosity in acetone is muchlower than could be expected in view of the slightly lower viscosity ofthe cellulose ether used as a starting material.

The appropriate molar ratio [aliphatic carboxylic acid/anhydroglucoseunits of cellulose ether] depends on the viscosity of the celluloseether used as a starting material. When the viscosity of the celluloseether used as a starting material is from 1.9-2.33 mPa·s, measured as a2.0 wt % solution in water at 20° C., the molar ratio [aliphaticcarboxylic acid/anhydroglucose units of cellulose ether] is generally2.8/1.0 or more, preferably 3.0/1.0 or more, more preferably 4.0/1.0 ormore, and most preferably 5.0/1.0 or more. As illustrated by theExamples, when the viscosity of the cellulose ether used as a startingmaterial is, e.g., 2.25 mPa·s, measured as a 2.0 wt % solution in waterat 20° C., typically a weight ratio of 4.0/1.0 or more is appropriatefor obtaining the esterified cellulose ethers of the present invention.On the other hand, when the viscosity of the cellulose ether used as astarting material is, e.g., 2.0 mPa·s, typically a weight ratio of3.0/1.0 or more suffices for obtaining the esterified cellulose ethersof the present invention. When the viscosity of the cellulose ether usedas a starting material is only 1.2-1.8 mPa·s, measured as a 2.0 wt %solution in water at 20° C., the molar ratio [aliphatic carboxylicacid/anhydroglucose units of cellulose ether] can be even lower, suchas. 1.5/1 or more, typically 1.7/1 or more, more typically 1.9/1 ormore, while still preparing esterified cellulose ethers which have aviscosity of only up to 13 mPa·s, measured as a 10 wt % solution of theesterified cellulose ether in acetone at 20° C.

If an esterified cellulose ether is obtained which has a too highviscosity, measured as a 10 wt % solution in acetone, the molar ratio[aliphatic carboxylic acid/anhydroglucose units of cellulose ether]should be increased and/or the viscosity of the cellulose ether used asa starting material, measured as a 2.0 wt % solution in water at 20° C.,should be decreased in line with the present teaching.

The upper limit of the [aliphatic carboxylic acid/anhydroglucose unitsof cellulose ether] is not critical for obtaining the esterifiedcellulose ethers of the present invention. However, to achieve areasonably high molecular weight, which is often desired, the molarratio [aliphatic carboxylic acid/anhydroglucose units of celluloseether] preferably is up to 11.5/1.0 or up to 10.0/1.0 or up to 8.0/1.0.The higher the molar ratio [aliphatic carboxylic acid/anhydroglucoseunits of cellulose ether] is, the lower is generally the weight averagemolecular weight of the esterified cellulose ethers, if the otherreaction parameters are kept constant. When the weight average molecularweight of an esterified cellulose ether increases, this typically meansthat its viscosity in acetone also increases. However, it has verysurprisingly been found that when cellulose ethers are used as astarting material which have a viscosity of only 1.20 to 2.0 mPa·s, morepreferably from 1.20 to 1.80 mPa·s, and most preferably from 1.20 to1.60 mPa·s, measured as a 2.0 wt % solution in water at 20° C.,esterified cellulose ethers can be produced which have a high weightaverage molecular weight but still a low viscosity in acetone.

The esterification reaction is generally conducted in the presence of anesterification catalyst, preferably in the presence of an alkali metalcarboxylate, such as sodium acetate or potassium acetate. The molarratio [alkali metal carboxylate/anhydroglucose units of cellulose ether]is generally from [0.4/1.0] to [3.8/1.0], and preferably from [0.6/1.0]to [2.7/1.0]. The higher the molar ratio [alkali metalcarboxylate/anhydroglucose units of cellulose ether] is, the higher isgenerally the weight average molecular weight of the esterifiedcellulose ethers, if the other reaction parameters are kept constant inthe defined ranges. If an esterified cellulose ether is obtained whichhas a too high viscosity, measured as a 10 wt % solution in acetone, themolar ratio [alkali metal carboxylate/anhydroglucose units of celluloseether] should be decreased and/or the molar ratio [aliphatic carboxylicacid/anhydroglucose units of cellulose ether] should be increased and/orthe viscosity of the cellulose ether used as a starting material,measured as a 2.0 wt % solution in water at 20° C., should be decreasedin line with the present teaching.

The reaction mixture is generally heated at 60° C. to 110° C.,preferably at 70 to 100° C., for a period of time sufficient to completethe reaction, that is, typically from 2 to 25 hours, more typically from2 to 8 hours. The reaction mixture should be thoroughly mixed to providea homogeneous reaction mixture. After completion of the esterificationreaction, the reaction product can be precipitated from the reactionmixture in a known manner, for example by contacting it with a largevolume of water, such as described in U.S. Pat. No. 4,226,981,International Patent Application WO 2005/115330 or European PatentApplication EP 0 219 426. In a preferred embodiment of the invention thereaction product is precipitated from the reaction mixture as describedin U.S. Provisional Application 61/616,207, filed 27 Mar. 2012 or in itscorresponding International Patent Application PCT/US13/030394,published as WO2013/148154.

Another aspect of the present invention is a composition comprising aliquid diluent and one or more of the above described esterifiedcellulose ethers. The term “liquid diluent” as used herein means adiluent that is liquid at 25° C. and atmospheric pressure. The diluentcan be water or an organic liquid diluent or a mixture of water and anorganic liquid diluent. Preferably the amount of the liquid diluent issufficient to provide sufficient fluidity and processability to thecomposition for the desired usage, such as spray-drying or for coatingpurposes.

The term “organic liquid diluent” as used herein means an organicsolvent or a mixture of two or more organic solvents. Preferred organicliquid diluents are polar organic solvents having one or moreheteroatoms, such as oxygen, nitrogen or halogen like chlorine. Morepreferred organic liquid diluents are alcohols, for examplemultifunctional alcohols, such as glycerol, or preferably monofunctionalalcohols, such as methanol, ethanol, isopropanol or n-propanol; ethers,such as tetrahydrofuran, ketones, such as acetone, methyl ethyl ketone,or methyl isobutyl ketone; acetates, such as ethyl acetate; halogenatedhydrocarbons, such as methylene chloride; or nitriles, such asacetonitrile.

In one embodiment the composition of the present invention comprises asliquid diluent an organic diluent alone or mixed with a minor amount ofwater. In this embodiment the composition of the present inventionpreferably comprises more than 50, more preferably at least 65, and mostpreferably at least 75 weight percent of an organic liquid diluent andpreferably less than 50, more preferably up to 35, and most preferablyup to 25 weight percent of water, based on the total weight of theorganic liquid diluent and water. This embodiment of the invention is ofparticularly useful if the present invention comprises an activeingredient of poor water solubility.

In another embodiment the composition of the present invention comprisesas liquid diluent water alone or mixed with a minor amount of an organicliquid diluent as described above. In this embodiment the composition ofthe present invention preferably comprises at least 50, more preferablyat least 65, and most preferably at least 75 weight percent of water andpreferably up to 50, more preferably up to 35, and most preferably up to25 weight percent of an organic liquid diluent, based on the totalweight of the organic liquid diluent and water. This embodiment of theinvention is particularly useful for providing coatings or capsules fromaqueous compositions comprising the esterified cellulose ether of thepresent invention. When preparing an aqueous solution, it is preferredthat at least a portion of the groups of formula —C(O)—R—COOA are intheir salt form.

The composition of the present invention comprising a liquid diluent andone or more of the above described esterified cellulose ethers is usefulas an excipient system for active ingredients and particularly useful asan intermediate for preparing an excipient system for activeingredients, such as fertilizers, herbicides or pesticides, orbiologically active ingredients, such as vitamins, herbals and mineralsupplements and drugs. Accordingly, the composition of the presentinvention preferably comprises one or more active ingredients, mostpreferably one or more drugs. The term “drug” is conventional, denotinga compound having beneficial prophylactic and/or therapeutic propertieswhen administered to an animal, especially humans. Preferably, the drugis a “low-solubility drug”, meaning that the drug has an aqueoussolubility at physiologically relevant pH (e.g., pH 1-8) of about 0.5mg/mL or less. The invention finds greater utility as the aqueoussolubility of the drug decreases. Thus, compositions of the presentinvention are preferred for low-solubility drugs having an aqueoussolubility of less than 0.1 mg/mL or less than 0.05 mg/mL or less than0.02 mg/mL, or even less than 0.01 mg/mL where the aqueous solubility(mg/mL) is the minimum value observed in any physiologically relevantaqueous solution (e.g., those with pH values between 1 and 8) includingUSP simulated gastric and intestinal buffers. The active ingredient doesnot need to be a low-solubility active ingredient in order to benefitfrom this invention, although low-solubility active ingredientsrepresent a preferred class for use with the invention. An activeingredient that exhibits appreciable aqueous solubility in the desiredenvironment of use may have an aqueous solubility up to 1 to 2 mg/mL, oreven as high as 20 to 40 mg/mL. Useful low-solubility drugs are listedin the International Patent Application WO 2005/115330, pages 17-22.

The liquid composition of the present invention preferably comprisesfrom 1 to 40 percent, more preferably from 5 to 35 percent, even morepreferably from 7 to 30 percent, most preferably from 10 to 25 percentof at least one esterified cellulose ether as described above, from 40to 99 percent, more preferably from 50 to 94.9 percent, even morepreferably from 65 to 92.5 percent and most preferably from 70 to 89percent of a liquid diluent described further above, and from 0 to 40percent, more preferably from 0.1 to 40 percent, even more preferablyfrom 0.5 to 25 percent, and most preferably from 1 to 15 percent of anactive ingredient, based on the total weight of the composition. The lowviscosity of the esterified cellulose ether, measured as a 10 wt %solution in acetone at 20° C., allows the incorporation of a highconcentration of the esterified cellulose ether, i.e., a high ratio ofesterified cellulose ether to liquid diluent, while still providing aliquid composition of reasonably low viscosity. This can be utilized intwo ways to produce solid dispersions of an active ingredient in anesterified cellulose ether: 1. Either the ratio of esterified celluloseether/active ingredient is kept the same as in known, more dilutecompositions. In this case a higher concentration of the esterifiedcellulose ether also leads to a higher concentration of the activeingredient in the liquid composition, and, accordingly to an increasedthroughput of the active ingredient in the production of soliddispersions while maintaining the same stability of the activeingredient. 2. Alternatively, only the concentration of the esterifiedcellulose ether in the liquid composition is increased, but not theconcentration of the active ingredient. This leads to a higher ratio ofesterified cellulose ether/active ingredient, which leads to an improvedstabilization of the active ingredient in the matrix of the esterifiedcellulose ether upon removal of the liquid diluent without decreasingthe throughput of the active ingredient. This means that formulators canoperate at a higher content of the esterified cellulose ether in theliquid formulation—without the need to reduce the content of the activeingredient—in order to achieve enhanced stabilization of the amorphousstate of an active ingredient in a solid dosage form. The esterifiedcellulose ethers of the present invention allow a high loading of theactive ingredient in the liquid composition while still achieving areasonably high throughput in preparing a solid dispersion. Theproduction of semi-ordered instead of amorphous dispersions to achieve ahigher active ingredient throughput as proposed in WO2004/014342, page13, last paragraph, is not necessary.

In one aspect of the invention the composition comprising at least oneesterified cellulose ether as described above, one or more activeingredients and optionally one or more adjuvants can be used in liquidform, for example in the form of a suspension, a slurry, a sprayablecomposition, or a syrup. The liquid composition is useful, e.g., fororal, ocular, topical, rectal or nasal applications. The liquid diluentshould generally be pharmaceutically acceptable, such as ethanol orglycerol, optionally mixed with water as described above. The lowviscosity of the esterified cellulose ether in acetone or anotherorganic solvent significantly improves the handling of the liquidcomposition, such as its ability of being poured or pumped.

In another aspect of the invention the liquid composition of the presentinvention is used for producing a solid dispersion comprising at leastone active ingredient, such as a drug described further above, at leastone esterified cellulose ether as described above and optionally one ormore adjuvants. The solid dispersion is produced by removing the liquiddiluent from the composition.

The low viscosity of the esterified cellulose ether in acetone oranother organic solvent allows the incorporation of a high concentrationof the esterified cellulose ether, and accordingly a high concentrationof a drug, into the composition while still maintaining a reasonably lowviscosity of the liquid composition. This is highly advantageous forachieving a high throughput when the liquid composition is used forcoating purposes or when the comprising the esterified cellulose etheris subjected to spray-drying, for example for preparing soliddispersions comprising an active ingredient and an esterified celluloseether. Moreover, liquid formulations using a high ratio of esterifiedcellulose ether to active ingredient, as described above, can beformulated with spray drying. A high ratio of esterified cellulose etherto active ingredient is desired in maintaining supersaturation of poorlysoluble active ingredients and for increasing its bioavailability.

One method of removing the liquid diluent from the liquid composition isby casting the liquid composition into a film or a capsule or byapplying the liquid composition onto a solid carrier that in turn maycomprise an active ingredient. The use of the liquid composition of thepresent invention for coating purposes is a preferred aspect of thepresent invention.

A preferred method of producing a solid dispersion is by spray-drying.The term “spray-drying” refers to processes involving breaking up liquidmixtures into small droplets (atomization) and rapidly removing solventfrom the mixture in a spray-drying apparatus where there is a strongdriving force for evaporation of solvent from the droplets. Spray-dryingprocesses and spray-drying equipment are described generally in Perry'sChemical Engineers' Handbook, pages 20-54 to 20-57 (Sixth Edition 1984).More details on spray-drying processes and equipment are reviewed byMarshall, “Atomization and Spray-Drying,” 50 Chem. Eng. Prog. Monogr.Series 2 (1954), and Masters, Spray Drying Handbook (Fourth Edition1985). A useful spray-drying process is described in the InternationalPatent Application WO 2005/115330, page 34, line 7-page 35, line 25.Alternatively, the solid dispersion of the present invention may beprepared by i) blending a) at least one esterified cellulose etherdefined above, b) one or more active ingredients and c) one or moreoptional additives, and ii) subjecting the blend to extrusion. The term“extrusion” as used herein includes processes known as injectionmolding, melt casting and compression molding. Techniques for extruding,preferably melt-extruding compositions comprising an active ingredientsuch as a drug are known and described by Joerg Breitenbach, Meltextrusion: from process to drug delivery technology, European Journal ofPharmaceutics and Biopharmaceutics 54 (2002) 107-117 or in EuropeanPatent Application EP 0 872 233. The solid dispersion of the presentinvention preferably comprises from 20 to 99.9 percent, more preferablyfrom 30 to 98 percent, and most preferably from 60 to 95 percent of anesterified cellulose ether a) as described above, and preferably from0.1 to 80 percent, more preferably from 2 to 70 percent, and mostpreferably from 5 to 40 percent of an active ingredient b), based on thetotal weight of the esterified cellulose ether a) and the activeingredient b). The combined amount of the esterified cellulose ether a)and the active ingredient b) is preferably at least 70 percent, morepreferably at least 80 percent, and most preferably at least 90 percent,based on the total weight of the solid dispersion. The remaining amount,if any, consists of one or more of the adjuvants c) as described below.The solid dispersion can comprise one or more of the esterifiedcellulose ethers a), one or more of the active ingredients b), andoptionally one or more of the adjuvants c), however their total amountis generally within the above-mentioned ranges.

Once the solid dispersion comprising at least one active ingredient inat least one esterified cellulose ether has been formed, severalprocessing operations can be used to facilitate incorporation of thedispersion into a dosage form. These processing operations includedrying, granulation, and milling. The inclusion of optional adjuvants inthe solid dispersion may be useful in order to formulate the compositioninto dosage forms. The solid dispersion of the present invention may bein various forms, such as in the form of strands, pellets, granules,pills, tablets, caplets, microparticles, fillings of capsules orinjection molded capsules or in the form of a powder, film, paste,cream, suspension or slurry.

The amount of the active ingredient in the dosage form is generally isat least 0.1 percent, preferably at least 1 percent, more preferably atleast 3 percent, most preferably at least 5 percent and generally up to70 percent, preferably up to 50 percent, more preferably up to 30percent, most preferably up to 25 percent, based on the total weight ofthe dosage form.

In another aspect of the invention the composition of the presentinvention comprising a liquid diluent and one or more of the abovedescribed esterified cellulose ethers may be used for coating dosageforms, such as tablets, granules, pellets, caplets, lozenges,suppositories, pessaries or implantable dosage forms, to form a coatedcomposition. If the composition of the present invention comprises anactive ingredient, such as a drug, drug layering can be achieved, i.e.,the dosage form and the coating may comprise different activeingredients for different end-uses and/or having different releasekinetics.

In yet another aspect of the invention the composition of the presentinvention comprising a liquid diluent and one or more of the abovedescribed esterified cellulose ethers may be used for the manufacture ofcapsules in a process which comprises the step of contacting the liquidcomposition with dipping pins.

The liquid composition and the solid dispersion of the present inventionmay further comprise optional additives, such as coloring agents,pigments, opacifiers, flavor and taste improvers, antioxidants, and anycombination thereof. Optional additives are preferably pharmaceuticallyacceptable. Useful amounts and types of one or more optional adjuvantsare generally known in the art and depend on the intended end-use of theliquid composition or the solid dispersion of the present invention.

Some embodiments of the invention will now be described in detail in thefollowing Examples.

EXAMPLES

Unless otherwise mentioned, all parts and percentages are by weight. Inthe Examples the following test procedures are used.

Viscosity of Hydroxypropyl Methyl Cellulose (HPMC) Samples

The viscosity of the HPMC samples was measured as a 2.0% by weightsolution in water at 20° C.±0.1° C. The 2.0% by weight HPMC solution inwater was prepared according to United States Pharmacopeia (USP 35,“Hypromellose”, pages 3467-3469), followed by an Ubbelohde viscositymeasurement according to DIN 51562-1:1999-01 (January 1999).

Viscosity of Hydroxypropyl Methyl Cellulose Acetate Succinate (HPMCAS)

The 2.0% by weight solution of the HPMCAS in 0.43 wt % aqueous NaOH wasprepared as described in“Hypromellose Acetate Succinate, United StatesPharmacopia and National Formulary, NF 29, pp. 1548-1550”, followed byan Ubbelohde viscosity measurement at 20° C. according to DIN51562-1:1999-01 (January 1999).

The 10 wt % solution of the esterified cellulose ether in acetone wasprepared by first determining the loss on drying of the HPMCAS according“Hypromellose Acetate Succinate, United States Pharmacopia and NationalFormulary, NF 29, pp. 1548-1550”. Subsequently 10.00 g HPMCAS, based onits dry weight, was mixed with 100 g of acetone under vigorous stirringat room temperature. The mixture was rolled on a roller mixer for about24 hours. The solution was centrifuged at 2000 rpm for 3 minutes using aMegafuge 1.0 centrifuge, commercially available from Heraeus HoldingGmbH, Germany, followed by an Ubbelohde viscosity measurement at 20° C.according to DIN 51562-1:1999-01 (January 1999).

Content of Ether and Ester Groups of HPMCAS

The content of ether groups in the esterified cellulose ether wasdetermined in the same manner as described for “Hypromellose”, UnitedStates Pharmacopeia and National Formulary, USP 35, pp 3467-3469.

The ester substitution with acetyl groups (—CO—CH₃) and the estersubstitution with succinoyl groups (—CO—CH₂—CH₂—COOH) were determinedaccording to Hypromellose Acetate Succinate, United States Pharmacopiaand National Formulary, NF 29, pp. 1548-1550″. Reported values for estersubstitution were corrected for volatiles (determined as described insection “loss on drying” in the above HPMCAS monograph).

Determination of M_(w) M_(n) and M_(z) of HPMCAS

Mw, Mn and Mz were measured according to Journal of Pharmaceutical andBiomedical Analysis 56 (2011) 743 unless stated otherwise. The mobilephase was a mixture of 40 parts by volume of acetonitrile and 60 partsby volume of aqueous buffer containing 50 mM NaH2PO4 and 0.1 M NaNO3.The mobile phase was adjusted to a pH of 8.0. Solutions of the celluloseether esters were filtered into a HPLC vial through a syringe filter of0.45 μm pore size.

More specifically, the utilized Chemicals and solvents were:

Polyethylene oxide standard materials (abbreviated as PEOX 20 K and PEOX30 K) were purchased from Agilent Technologies, Inc. Palo Alto, Calif.,catalog number PL2083-1005 and PL2083-2005.

Acetonitrile (HPLC grade≧99.9%, CHROMASOL plus), catalog number 34998,sodium hydroxide (semiconductor grade, 99.99%, trace metal base),catalog number 306576, water (HPLC grade, CHROMASOLV Plus) catalognumber 34877 and sodium nitrate (99.995%, trace metal base) catalognumber 229938 were purchased from Sigma-Aldrich, Switzerland.

Sodium dihydrogen phosphate (≧99.999% TraceSelect) catalog number 71492was purchased from FLUKA, Switzerland.

The normalization solution of PEOX20 K at 5 mg/mL, the standard solutionof PEOX30 K at 2 mg/mL, and the sample solution of HPMCAS at 2 mg/mLwere prepared by adding a weighed amount of polymer into a vial anddissolving it with a measured volume of mobile phase. All solutions wereallowed to dissolve at room temperature in the capped vial for 24 h withstirring using a PTFE-coated magnetic stirring bar.

The normalization solution (PEOX 20 k, single preparation, N) and thestandard solution (PEOX30 K, double preparation, S1 and S2) werefiltered into a HPLC vial through a syringe filter of 0.02 μm pore sizeand 25 mm diameter (Whatman Anatop 25, catalog number 6809-2002),Whatman.

The test sample solution (HPMCAS, prepared in duplicate, T1, T2) and alaboratory standard (HPMCAS, single preparation, LS) were filtered intoa HPLC vial through a syringe filter of 0.45 μm pore size (Nylon, e.g.Acrodisc 13 mm VWR catalog number 514-4010).

Chromatographic condition and run sequence were conducted as describedby Chen, R. et al.; Journal of Pharmaceutical and Biomedical Analysis 56(2011) 743-748). The SEC-MALLS instrument set-up included a HP1100 HPLCsystem from Agilent Technologies, Inc. Palo Alto, Calif.; a DAWN HeleosII 18 angle laser light scattering detector and a OPTILAB rex refractiveindex detector, both from Wyatt Technologies, Inc. Santa Barbara, Calif.The analytical size exclusion column (TSK-GEL® GMPWXL, 300×7 8 mm) waspurchased from Tosoh Bioscience. Both the OPTILAB and the DAWN wereoperated at 35° C. The analytical SEC column was operated at roomtemperature (24±5° C.). The mobile phase was a mixture of 40 volumeparts of acetonitrile and 60 volume parts of aqueous buffer containing50 mM NaH2PO4 and 0.1 M NaNO3 prepared as follows:

Aqueous buffer: 7.20 g of sodium dihydrogen phosphate and 10.2 g ofsodium nitrate were added to 1.2 L purified water in a clean 2 L glassbottle under stirring until dissolution.

Mobile phase: 800 mL of acetonitrile were added to 1.2 L of the aqueousbuffer prepared above, and stirred until a good mixture was achieved andthe temperature equilibrated to ambient temperature.

The mobile phase was pH adjusted to 8.0 with 10M NaOH and filteredthrough a 0.2 m nylon membrane filter. The flow rate was 0.5 mL/min within-line degassing. The injection volume was 100 μL and the analysis timewas 35 min.

The MALLS data were collected and processed by Wyatt ASTRA software(version 5.3.4.20) using dn/dc value (refractive index increment) of0.120 mL/g for HPMCAS. The light scattering signals of detector Nos.1-4, 17, and 18) were not used in the molecular weight calculation. Arepresentative chromatographic run sequence is given below: B, N, LS, S1(5×), S2, T1 (2×), T2 (2×), T3 (2×), T4 (2×), S2, T5(2×), etc., S2, LS,W, where, B represents blank injection of mobile phase, N1 representsnormalization solution; LS represents a laboratory standard HPMCAS; S1and S2 represent standard solutions one and two, respectively; T1, T2,T3, T4, and T5 represent test sample solutions and W represents waterinjection. (2×) and (5×) denote the number of injections of the samesolution.

Both the OPTILAB and the DAWN were calibrated periodically according tothe manufacturer's recommended procedures and frequency. A 100 μLinjection of a 5 mg/mL polyethylene oxide standard (PEOX20 K) wasemployed for normalizing all angle light scattering detectors relativeto 90−detector for each run sequence.

Use of this mono-dispersed polymer standard also enabled the volumedelay between the OPTILAB and the DAWN to be determined, permittingproper alignment of the light scattering signals to the refractive indexsignal. This is necessary for the calculation of the weight-averagedmolecular weight (Mw) for each data slice.

Production of Hydroxypropyl Methyl Cellulose Acetate Succinate (HPMCAS)of Examples 1-16 and of Comparative Examples a to C

Glacial acetic acid, acetic anhydride, a hydroxypropyl methylcellulose(HPMC), succinic anhydride and sodium acetate (water free) wereintroduced in the amounts listed in Table 1 below into a reaction vesselunder thorough stirring to produce a homogeneous reaction mixture. TheHPMC had a methoxyl and hydroxypropoxyl substitution and a viscosity,measured as a 2% solution in water at 20° C., as listed in Table 2below.

The mixture was heated at 85° C. with agitation for 3 or 3.5 hours, aslisted in Table 1 below, to effect esterification. x L of water wasadded to the reactor under stirring to precipitate the HPMCAS. Theprecipitated product was removed from the reactor and washed with y L ofwater by applying high shear mixing using an Ultra-Turrax stirrerS50-G45 running at 5200 rpm. The washing was conducted in severalportions with intermediate filtration steps to obtain HPMCAS of veryhigh purity. The HPMCAS products should be washed and filtrated untiltheir viscosity is substantially constant (10 wt. % in acetone). Thenumbers of L of water x and y are listed in Table 1 below. After thelast filtration step the product was dried at 50° C. overnight.

Production of HPMCAS of Comparative Example D

The production of HPMCAS according to Comparative Example D was carriedout as in Examples 1 to 16, except that a HPMC of a higher viscosity wasused, as listed in Table 2 below. The HPMC is commercially availablefrom The Dow Chemical Company as Methocel E3 LV Premium cellulose ether.

Production of HPMCAS of Comparative Example E

The production of HPMCAS according to Comparative Example E was carriedout as in Examples 1 to 16, except that the type of HPMC and the weightratios of glacial acetic acid, acetic anhydride, HPMC, succinicanhydride and sodium acetate (water free) were used as disclosed inExample 2 of European Patent Application EP 0219 426 A2. The usedamounts are listed in Table 1 below.

The HPMC used in Comparative Example E had a viscosity of 3.1 mPa's,measured as a 2% solution in water at 20° C. The HPMC contained 9.3% byweight of hydroxypropoxyl groups and 28.2% by weight of methoxyl groups.This HPMC is commercially available from The Dow Chemical Company asMethocel E3 LV Premium cellulose ether.

The mixture was heated at 85° C. with agitation for 3.5 hours to effectesterification. x L of water was added to the reactor under stirring toprecipitate the HPMCAS. The precipitated product was removed from thereactor and washed with y L of water by applying high shear mixing usingan Ultra-Turrax stirrer S50-G45 running at 5200 rpm. The numbers ofwater x and y are listed in Table 1 below. The product was isolated byfiltration and dried at 55° C. for 12 h.

The obtained ester substitutions % acetyl and % succinoyl in ComparativeExample E was significantly different from those disclosed in Example 2of European Patent Application EP 0219 426 A2. Therefore, ComparativeExample E was repeated. The obtained ester substitutions % acetyl and %succinoyl in the repeated Example E were substantially the same as inthe first Comparative Example E. The results in Table 2 show the averageof the two runs of Comparative Example E.

Production of HPMCAS of Comparative Examples F and G

The production of HPMCAS according to Comparative Examples F and G wascarried out as in Examples 1 to 16, except that the weight ratios ofglacial acetic acid, acetic anhydride, HPMC, succinic anhydride andsodium acetate (water free) were used as disclosed International PatentApplication WO 2005/115330, pages 51 and 52, polymers 1 and 3. Theproduct was obtained, separated and washed as described in InternationalPatent Application WO 2005/115330. The reaction mixture was quenchedinto 2.4 L of water, precipitating the polymer. An additional 1 L ofwater was used to complete the precipitation for Comparative Example Fonly. The polymer was then isolated and washed with 3×300 mL of water.Then the polymer was dissolved in 600 mL of acetone and againprecipitated in 2.4 L of water. To complete precipitation another 1 L ofwater was added.

Comparative Examples H to J

As disclosed in International Patent Application WO 2011/159626 on pages1 and 2, HPMCAS is currently commercially available from Shin-EtsuChemical Co., Ltd. (Tokyo, Japan), known by the trade name “AQOAT”.Shin-Etsu manufactures three grades of AQOAT polymers that havedifferent combinations of substituent levels to provide entericprotection at various pH levels, AS-L, AS-M, and AS-H, typicallyfollowed by the designation “F” for fine or “G”, such as AS-LF or AS-LG.Their sales specifications are listed below. Samples of the commerciallyavailable materials were analyzed as described further above.

Designation of analyzed commercial samples: Comparative Example H I JPublished Composition of AQOAT polymers (wt %) Substituent contentL-Grade M-Grade H-Grade Methoxyl 20.0-24.0 21-0-25.0 22.0-26.0Hydroxypropoxyl 5.0-9.0 5.0-9.0  6.0-10.0 Acetyl 5.0-9.0  7.0-11.010.0-14.0 Succinoyl 14.0-18.0 10-14 4.0-8.0

Samples of the commercially available materials were analyzed asdescribed further above.

Comparative Examples K, L-1, L-2, M-1 and M-2

HPMCAS samples were produced as described on pages 34 and 35 of WO2011/159626. In Comparative Example K the recipe for HPMCAS-K(1) in WO2011/159626 was exactly repeated. In Comparative Examples L-1 and L-2the recipe for HPMCAS-K(2) and in Comparative Examples M-1 and M-2 therecipe for HPMCAS-K(3) in WO 2011/159626 were exactly repeated.Comparative Examples L and M were each conducted twice and reported asL-1, L-2, M-1 and M-2 respectively since the results in ComparativeExamples L-1 and M-1 for DOS_(Ac) and DOS_(s) deviated from the resultsreported in WO 2011/159626 for HPMCAS-K(2) and HPMCAS-K(3).

The properties of the HPMCAS produced according to Examples 1-16 andcomparative Examples A-F, K, L-1, L-2, M-1 and M-2 and the properties ofthe commercially available Comparative Examples H to J are listed inTable 2 below.

In Table 2 below the abbreviations have the following meanings:

DS_(M)=DS(methoxyl): degree of substitution with methoxyl groups;MS_(HP)=MS(hydroxypropoxyl): molar subst. with hydroxypropoxyl groups;DOS_(Ac): degree of subst. of acetyl groups; DOS_(s): degree of subst.of succinoyl groups.

TABLE 1 HPMC, 2% acetic Succinic Acetic Sodium Table 1 viscosity acidanhydride anhydride acetate Heating (Comp.) HPMC* in water mol/molmol/mol mol/mol mol/mol at 85° C. x L of y L of Example g Mol (mPa · s)g HPMC g HPMC g HPMC g HPMC hours water water 1 50.0 0.25 2.25 113.37.64 14.0 0.57 65.0 2.69 50.0 2.47 3.5 0.6 14 2 50.0 0.25 2.25 93.3 6.3014.0 0.57 65.0 2.69 50.0 2.47 3.5 0.6 14 3 50.0 0.25 2.25 83.3 5.62 14.00.57 65.0 2.69 50.0 2.47 3.5 0.6 14 4 50.0 0.25 2.25 76.7 5.18 14.0 0.5765.0 2.69 50.0 2.47 3.5 0.6 10 5 50.0 0.25 2.25 76.0 5.13 5.5 0.22 46.741.93 50.0 2.47 3.0 0.46 32 A 35.0 0.17 2.25 38.5 3.71 3.85 0.22 32.71.93 35.0 2.47 3.0 0.46 32 6 35.0 0.17 2.25 53.2 5.13 5.9 0.34 21.7 1.2814.48 1.02 3.5 0.47 17 B 35.0 0.17 2.25 38.5 3.71 5.9 0.34 21.7 1.2814.48 1.02 3.5 0.47 27 7 35.0 0.17 2.25 88.26 8.51 16.3 0.94 37.33 2.2029.75 2.10 2.8 0.33 22 C 35.00 0.17 2.25 38.50 3.71 9.8 0.57 45.50 2.6935.00 2.47 3.5 0.42 27 D 195.0 0.97 3.1 442.0 7.6 54.6 0.57 253.5 2.69195.0 2.47 3.5 1.8 35 8 50.0 0.25 1.5 113.3 7.6 14.0 0.57 65.0 2.69 50.02.47 3.5 0.6 12 9 50.0 0.25 1.5 100.0 6.7 14.0 0.57 65.0 2.69 50.0 2.473.5 0.6 10 10 40.0 0.20 1.5 74.6 6.29 11.2 0.57 52.0 2.69 40.0 2.47 3.50.6 10 11 215 1.06 1.5 231 3.6 35.5 0.33 130.2 1.25 86.94 1.00 3.5 3.0611 12 60 0.3 1.39 35 2.0 10.1 0.34 37.2 1.28 17.4 0.72 3.5 0.8 27 13 600.3 1.39 30 1.7 10.1 0.34 37.2 1.28 17.4 0.72 3.5 0.8 29 14 100 0.49 2.0135 4.5 16.9 0.34 62 1.28 41.4 1.02 3.5 1.33 6.3 15 100 0.49 2.0 126 4.316.9 0.34 62 1.28 41.4 1.02 3.5 1.33 6.3 16 100 0.49 2.0 117 4 16.9 0.3462 1.28 41.4 1.02 3.5 1.33 6.8 E 200 0.96 3.1 600 10.2 50.0 0.51 76 0.78160 1.97 3.5 2.4 11 F 80 0.40 3.1 420 17.7 18.9 0.48 640.2 16.53 40.431.25 21.75 See Comp. G 80 0.40 3.1 420 17.7 13.2 0.33 432.8 11.17 40.431.25 21.75 Examples F and G above *calculated on the dried basis

TABLE 2 10% 2% viscosity viscosity Ether Ester Table 2 Molecular weightin in Substitution substitution Ether Ester (Comp.) (kDA) acetone NaOHMethoxyl Hydroxy- Acetyl Succinoyl Substitution substitution Example MnMw Mz (mPa · s) (mPa · s) (%) Propoxyl, % (%) (%) DS_(M) MS_(HP)DOS_(Ac) DOS_(s) 1 15 30 77 7.83 2.03 23.9 7.1 9.4 13.1 2.03 0.25 0.580.34 2 16 38 127 8.84 2.04 23.8 7.0 9.4 13.1 2.02 0.25 0.57 0.34 3 17 45178 9.98 2.04 23.8 7.0 9.6 13.2 2.03 0.25 0.59 0.34 4 17 48 194 9.202.04 23.8 7.0 9.7 13.1 2.03 0.25 0.60 0.34 5 15 34 101 8.60 2.20 24.97.4 11.0 6.8 1.98 0.24 0.63 0.17 A 29 128 747 65.0 2.17 24.6 7.3 11.06.8 1.95 0.24 0.63 0.17 6 15 38 129 6.92 2.17 24.5 7.3 9.0 10.5 2.000.25 0.53 0.26 B 20 80 403 15.1 2.18 24.4 7.2 7.9 10.9 1.96 0.24 0.460.27 7 18 33 99 9.17 2.21 23.4 7.0 6.4 16.6 1.99 0.25 0.39 0.43 C 31 189988 insoluble 2.07 23.1 6.9 9.5 12.1 1.92 0.24 0.57 0.31 D 36 139 154037.4 2.61 22.7 7.5 11.0 12.1 1.94 0.26 0.68 0.32 8 9 14 28 1.79 1.4623.3 7.0 9.6 12.9 1.97 0.24 0.58 0.33 9 9 15 29 2.05 1.43 23.4 7.0 9.713.1 1.99 0.25 0.59 0.34 10 9 14 28 1.86 1.44 23.30 7.00 9.8 13.2 1.980.25 0.60 0.34 11 11 24 75 1.97 1.60 23.1 7.8 10.0 11.3 1.93 0.27 0.600.29 12 10 41 185 1.81 1.49 22.7 7.7 9.8 12.3 1.91 0.27 0.59 0.32 13 12112 863 2.41 1.49 22.7 7.7 10.2 11.6 1.90 0.27 0.62 0.30 14 16 68 3377.9 2.0 23.4 7.8 9.1 11.5 1.94 0.27 0.54 0.29 15 20 105 649 8.5 2.0 23.37.8 9.4 11.7 1.94 0.27 0.56 0.30 16 28 158 950 10.4 2.0 23.1 7.9 9.311.4 1.91 0.27 0.56 0.29 E 26 65 329 16.6 2.89 22.9 7.3 5.7 16.0 1.910.25 0.34 0.41 F 23 51 462 12.8 2.86 22.3 7.40 11.7 11.7 1.90 0.26 0.720.31 G 22 54 1158 13.5 2.86 22.6 7.1 12.6 9.1 1.87 0.24 0.75 0.23 H 33153 889 27.7 3.0 22.5 7.0 8.1 14.7 1.90 0.24 0.49 0.38 I 27 114 654 22.92.94 23.1 7.3 9.3 10.6 1.88 0.24 0.54 0.26 J 29 137 821 29.8 2.89 23.67.2 11.6 7.9 1.90 0.24 0.67 0.19 K 94 427 2592 insoluble 2.06 15.7 6.212.1 20.8 1.47 0.24 0.82 0.60 L-1 recovery rate only partially 2.05 16.26.3 14.3 16.6 1.47 0.24 0.94 0.46 71% insoluble L-2 recovery rate onlypartially 1.97 15.8 6.0 14.8 17.1 1.45 0.23 0.98 0.48 71% insoluble M-I39 234 2701 partially 1.92 17.2 6.6 19.1 8.2 1.49 0.24 1.19 0.22insoluble M-2 25 143 2280 partially 1.81 16.9 6.4 19.0 8.7 1.47 0.231.19 0.23 insoluble

The comparison between Example 5 and Comparative Example A, thecomparison between Example 6 and Comparative Example B and thecomparison between Example 7 and Comparative Example C illustrate thatthe use of a cellulose ether which has a viscosity of less than 2.33mPa·s, measured as a 2.0 wt % solution in water at 20° C., does notautomatically lead to the cellulose ethers of the present invention.When an aliphatic carboxylic acid is used as a reaction diluent, theviscosity of the esterified cellulose ether, measured as a 10 wt %solution in acetone at 20° C., can be varied by varying the molar ratio[aliphatic carboxylic acid/anhydroglucose units of cellulose ether] inthe esterification process. In Examples 5, 6 and 7 a higher molar ratio[aliphatic carboxylic acid/anhydroglucose units of cellulose ether] isused than in Comparative Examples A, B and C, while the other parametersare kept constant. Comparative Examples A, B and C are not prior artexamples although they are not within the scope of the presentinvention.

The comparison between Example 1 and Comparative Example D illustratesthat cellulose ethers having a viscosity of 3 mPa·s, measured as a 2.0wt % solution in water at 20° C., are not useful for preparing theesterified cellulose ethers of the present invention. The reactionconditions and the ratios between the reactants in Comparative Example Dare essentially the same as those in Example 1, but the producedesterified cellulose ether of Comparative Example D has a much higherviscosity, measured as a 10 wt % solution in acetone at 20° C., thanExample 1.

Examples 8-13 illustrate esterified cellulose ethers that have a verylow viscosity, measured as a 10 wt % solution in acetone at 20° C. Theseesterified cellulose ethers enable a very fast throughput inspray-drying operations.

Examples 13, 15 and 16 illustrate how esterified cellulose ethers can beachieved which have a very surprising combination of high molecularweights and low viscosities, both measured as a 10 wt % solution inacetone at 20° C. and measured as a 2.0 wt % solution of the esterifiedcellulose ether in 0.43 wt % aqueous NaOH at 20° C.

The HPMCAS of Comparative Examples I, J-1, J-2, K-1 and K-2 were not oronly partially soluble in acetone at a concentration of 10 wt-%. InComparative Examples J-1 and J-2 the recovery rate in the utilized HPLCmethod was too low to make a reasonably reliable M_(w), M_(n) and M_(z)determination. Recovery rate=[weight of HPMCAS recovered from HPLCcolumn/weight of HPMCAS introduced into HPLC column]×100.

Impact of Cellulose Ethers on the Aqueous Solubility of a Poorly SolubleDrug

The ability of the esterified cellulose ethers of Examples 4 to 7 and 10and of Comparative Examples A-C and H-I to maintain drug concentrationsin an aqueous solution at supersaturation levels was tested with thepoorly water soluble drugs Griseofulvin and Phenytoin.

Griseofulvin has a water solubility of 8.54 mg/1, a log P of 2.2, a Tmof 220° C., a Tg of 85° C., and, accordingly a Tm/Tg=493° K/358° K=1.39.[Feng, Tao et. al.; J. Pharm. Sci.; Vol. 97, No. 8, 2008, pg 3207-3221and W. Curatolo, Pharmaceutical Research, Vol. 26, No. 6, June 2009, pg1422]. Griseofulvin belongs to group 2 on the map TmITg ratio versus logP (FIG. 14 on page 1018 in MOLECULAR PHARMACEUTICS VOL. 5, NO. 6).

Phenytoin has a water solubility of 32 mg/1, a log P of 2.47, a Tm of295° C., a Tg of 71° C. and, accordingly a Tm/Tg=568° K/344° K=1.65[Friesen et al., MOLECULAR PHARMACEUTICS VOL. 5, NO. 6, 1003-1019 and W.Curatolo, Pharmaceutical Research, Vol. 26, No. 6, June 2009, pg 1422].Phenytoin belongs to group 3 on the map Tm/Tg ratio versus log P (FIG.14 on page 1018 in MOLECULAR PHARMACEUTICS VOL. 5, NO. 6, 2008).

Solutions of an esterified cellulose ether listed in Table 3 below (950μl, 3.16 mg/L) in phosphate buffered saline (82 mM sodium chloride, 20mM sodium phosphate dibasic, 47 mM potassium phosphate monobasic, 0.5 wt% simulated intestinal fluid powder, pH 6.5) at 37° C. were roboticallydelivered into designated 1 mL vials arranged in an aluminum 96 (8×12)well block heated to 37° C. using a Tecan 150 liquid handler. Organicdrug solutions at 37° C. were dispensed onto the phosphate bufferedsaline aqueous solution comprising an esterified cellulose ether listedin Table 3 below. The organic drug solution was a) 20 g/L griseofulvinin dimethylformamide, 50 μL, final maximum drug concentration of 1000mg/L, or b) 20 g/L phenytoin in dimethylformamide, 50 μL, final maximumdrug concentration of 1000 mg/L. The robot aspirated and dispensedliquid in a set sequence for each vial for about 30 s to mix. After 180minutes the vials were centrifuged 1 min at about 3200×g(g=gravitational force on earth). An aliquot (30 μl) was transferred tomethanol (150 μl) in a 96-well plate, sealed, briefly gently agitated tomix, and then the drug concentration was analyzed by HPLC.

In a Control Run an experiment was separately carried out as describedabove with a phosphate buffered saline aqueous solution which did notcontain any amount of cellulose ether.

In Table 3 below the concentrations (averages of four experimentalreplicates) of Griseofulvin and Phenytoin are listed that have notprecipitated upon centrifugation after 180 minutes but that remaindissolved in the phosphate buffered saline aqueous solution. The errormargins of the concentrations are about 10%.

The results in Table 3 below illustrate that the esterified celluloseethers of the present invention are able to maintain the concentrationof poorly water-soluble drugs in an aqueous solution at supersaturationlevels. When comparing groups of esterified cellulose ethers of theExamples and Comparative Examples which have comparable acetyl andsuccinoyl substitutions, the data in Table 3 illustrates that theesterified cellulose ethers of the present invention have essentiallythe same ability to maintain drugs in supersaturation as comparableknown esterified cellulose ethers, even when the esterified celluloseethers of the present invention have a significantly lower viscosity,measured as a 10 wt. % solution in acetone, and a significantly lowerweight average molecular weight. This finding is highly surprising andillustrates the great advantages of the esterified cellulose ethers ofthe present invention as excipients for active ingredients of lowwater-solubility. The esterified cellulose ethers of the presentinvention combine easy processability in solutions, particularly inorganic solutions, and high ability to maintain the concentration ofpoorly water-soluble drugs in an aqueous solution at supersaturationlevels.

The HPMCAS of Example 5 has essentially the same ability to maintaindrugs in supersaturation and similar acetyl and succinoyl substitutionsas the HPMCAS of Comparative Examples A and J, although the HPMCAS ofExample 5 has a much lower weight average molecular weight and a muchlower viscosity, measured as a 10 wt. % solution in acetone. The sameobservation can be made when comparing Example 6 with ComparativeExamples B and I. The HPMCAS of Example 6 has the same or even a betterability to maintain drugs in supersaturation. A similar observation canbe made when comparing Examples 4 and 10 with Comparative Example C. TheHPMCAS of Examples 4 and 10 have a somewhat lower ability to maintainGriseofulvin at supersaturation levels, but the HPMCAS of ComparativeExample C does not dissolve at 10 wt. % in acetone. The HPMCAS ofExample 7 has essentially the same ability to maintain drugs insupersaturation as the HPMCAS of Comparative Example H, although theHPMCAS of Example 7 has a much lower weight average molecular weight anda much lower viscosity, measured as a 10 wt. % solution in acetone, thanthe HPMCAS of Comparative Example H.

TABLE 3 2% 10% Griseofulvin Phenytoin Hydroxy- viscosity viscosityconcentration concentration (Comp.) Methoxyl Propoxyl Acetyl Succinoylin NaOH Mn Mw Mz in acetone [mg/L] at [mg/L] at Example (%) (%) (%) (%)[mPa · s] [kDa] [kDa] [kDa] [mPa · s] 180 min. 180 min. 5 24.9 7.4 11.06.8 2.20 15 34 101 8.6 1100 520 A 24.6 7.3 11.0 6.8 2.17 29 128 747 651050 520 J 23.6 7.2 11.6 7.9 2.89 29 137 821 29.8 1060 500 6 24.5 7.39.0 10.5 2.17 15 38 129 6.9 770 310 B 24.4 7.2 7.9 10.9 2.18 20 80 40315.1 570 280 I 23.1 7.3 9.3 10.6 2.94 27 114 654 26.5 800 270 7 23.4 7.06.4 16.6 2.21 18 33 99 9.2 370 260 H 22.5 7.0 8.1 14.7 3.00 33 153 88927.7 360 230 4 23.8 7.0 9.7 13.1 2.04 17 48 194 9.20 830 300 10 23.3 7.09.8 13.2 1.44 9 14 28 1.86 810 350 C 23.1 6.9 9.5 12.1 2.07 31 189 988insoluble 1000 340 Control — — — — — — — — — 128 65

1. An esterified cellulose ether comprising (i) aliphatic monovalentacyl groups or (ii) groups of the formula —C(O)—R—COOA, wherein R is adivalent aliphatic or aromatic hydrocarbon group and A is hydrogen or acation, or (iii) a combination of aliphatic monovalent acyl groups andgroups of the formula —C(O)—R—COOA, having a viscosity of up to 2.33mPa·s, measured as a 2.0 wt % solution of the esterified cellulose etherin 0.43 wt % aqueous NaOH at 20° C., and having a viscosity of up to 13mPa·s, measured as a 10 wt % solution of the esterified cellulose etherin acetone at 20° C.
 2. The esterified cellulose ether of claim 1 havinga viscosity of from 1.20 to 1.80 mPa·s, measured as a 2.0 wt % solutionof the esterified cellulose ether in 0.43 wt % aqueous NaOH at 20° C. 3.The esterified cellulose ether of claim 1 or 2 having a viscosity of upto 10 mPa·s, measured as a 10 wt % solution of the esterified celluloseether in acetone at 20° C.
 4. The esterified cellulose ether of claim 3having a viscosity of up to 3 mPa·s, measured as a 10 wt % solution ofthe esterified cellulose ether in acetone at 20° C.
 5. The esterifiedcellulose ether of any one of claims 1 to 4 wherein the aliphaticmonovalent acyl groups are acetyl, propionyl or butyryl groups and thegroups of the formula —C(O)—R—COOA are —C(O)—CH₂—CH₂—COOA,—C(O)—CH═CH—COOA, or —C(O)—C₆H₄—COOA groups.
 6. The esterified celluloseether of any one of claims 1 to 5 being an esterified hydroxyalkylmethyl cellulose.
 7. The esterified cellulose ether of any one of claims1 to 6 being hydroxypropyl methyl cellulose acetate succinate.
 8. Acomposition comprising a liquid diluent and at least one esterifiedcellulose ether of any one of claims 1 to
 7. 9. The composition of claim8 additionally comprising at least one active ingredient and optionallyone or more adjuvants.
 10. The composition of claim 8 or 9 comprisingfrom 10 to 25 percent of at least one esterified cellulose ether, from70 to 89 percent of a liquid diluent, and from 1 to 15 percent of anactive ingredient, based on the total weight of the composition.
 11. Asolid dispersion comprising at least one active ingredient and at leastone esterified cellulose ether of any one of claims 1 to
 7. 12. Thesolid dispersion of claim 11 wherein the solid dispersion has beenformulated into tablets, pills, granules, pellets, caplets,microparticles, fillings of capsules, or into a paste, cream, suspensionor slurry.
 13. A dosage form being coated with at least one esterifiedcellulose ether of any one of claims 1 to
 7. 14. A capsule shellcomprising at least one esterified cellulose ether of any one of claims1 to 7.